ES2952192T3 - Method for solubilizing 5-amino-2,3-dihydrophthalazine-1,4-dione - Google Patents

Abstract

The present invention relates to a method for solubilizing 5-amino-2,3-dihydro-1,4-phthalazindione or its salts, to the solubilisate produced by this method and to their respective uses in pharmaceutical dosage forms. A solubilization method based on phosphatidylcholine is disclosed. (Automatic translation with Google Translate, without legal value)

Description

DESCRIPTION

Method for solubilizing 5-amino-2,3-dihydrophthalazine-1,4-dione

The present invention relates to a method for solubilizing 5-amino-2,3-dihydrophthalazine-1,4-dione or its salts, to the solubilizer produced by this method, its uses and a pharmaceutical composition containing said solubilizer.

Background of the invention

For decades, crime scene investigators have used 5-amino-2,3-dihydrophthalazine-1,4-dione (luminol) to detect blood traces, even if someone has tried to clean or erase them (Barni et al., Talanta 2007, 72, 896-913). The intensive luminescence upon oxidation catalyzed by iron in hemoglobin makes luminol a highly sensitive sensor. Since the first publication on the synthesis of luminol (A. J. Schmitz, Über das Hydrazid der Trimesinsaure und der Hemimellithsaure, Heidelberg, 1902) numerous other applications from environmental to medical have been established apart from its forensic use. For example, luminol is used for the detection of heavy metals or for biosensing in bioanalytical chemistry (Klopf and Nieman, Anal. Chem. 1983, 55, 1080-1083).

Alkali salts of luminol were structurally characterized only recently (Guzei et al., J. Coord. Chem.

2013, 66, 3722-3739), since sodium salt regained interest due to its pharmaceutical activity. Sodium luminolate demonstrates great potential in the immunomodulatory treatment of inflammatory and autoimmune diseases. Furthermore, sodium luminolate demonstrates extensive polymorphism with three crystal structures characterized until then (WO 2011/107295 A1; WO 2016/096143 A1).

Also for luminol itself, two crystalline forms have been reported (Paradies, Ber. Bunsen-Ges. Phys. Chem 1992, 96, 1027-1031; WO 2017/140430 A1). The general physicochemical properties of isomeric forms of luminol in aqueous solutions have been revealed by Skripnikova et al. (2017; J Mol Struct 1154: 59-63). Special therapeutic uses for these crystalline forms of Na-luminolate or luminol have been described in WO 2017/202496 A1. It is known that the crystalline forms of a compound can present different physical characteristics, such as solubility, dissolution rate and stability (cf. Haleblian und McCrone (1969): Journal of Pharmaceutical Sciences, 58: 911-929). These properties can influence the pharmaceutical processing of a compound, as well as its bioavailability and pharmacokinetics and, therefore, its biological efficacy (see Griesser (2006) in: Polymorphisms in the pharmaceutical industry. Hilfiker (Ed.) 21 1 -2. 3. 4). A formulation for increasing the oral bioavailability of drugs by adding at least one piperine to the solution was disclosed in WO 2013/108254 A1.

While the luminol salts described so far are easily soluble in water, luminol itself is poorly soluble in water. Additionally, the small amount that can be resolved tends to precipitate after a few days. Sensitivity to light, high temperatures and metal cations has also been described. This seriously hinders the use of aqueous luminol solutions. The problem can be overcome by using a basic solution or by using a diluent such as ethanol or DMSO. However, these diluents are not acceptable for a wide variety of pharmaceutical applications.

The use of the sodium salt of luminol is advantageous with respect to solubility in an aqueous medium. However, for absorption in the gastrointestinal tract, topical applications for transdermal delivery or for transport across the blood-brain barrier, it would be preferable if the free acid could be administered to increase the bioavailability of luminol. Therefore, sufficiently high plasma and intracellular concentrations could be achieved to maximize the therapeutic potential of luminol. Therefore, there is a need to find a method to solubilize luminol in an aqueous medium.

There are a variety of approaches to improve the solubility of lipophilic pharmaceutical agents and, in many cases, also their bioavailability through the use of solubilization techniques. Here, the solubility of an agent in a medium is increased by the addition of a third substance. These third substances are called solubilizers (solubilizing agents), substances that can, for example, form a complex with the substance to be solubilize. Examples of such chelating agents are sodium benzoate and sodium salicylate. Another mechanism of action of solubilizers is to increase the dissolution capacity of the solvent, for example, by altering the water cluster structure. Examples of such structure breakers are glycerol (glycerin) and macrogols (polyethylene glycol, PEG).

A third solubilization mechanism is micelle and liposome application technologies. They have gained wide attention in recent decades. Here, the substance to be administered is enclosed in a spherical aggregate of surfactant molecules. These molecules are characterized by a polar head group and a long nonpolar chain ("tail"). When administered in an aqueous medium, these molecules tend to associate and aggregate to spherical structures, orienting the polar head group towards the surrounding medium and the non-polar chain towards the interior of the spheres. When these spheres consist of a single layer of such amphiphilic molecules they are called micelles. Depending on the nature of the amphiphilic molecule and the reaction conditions, it is also possible to form spheres with more than one layer. Here a second layer is formed within the outer shell of the sphere, the non-polar groups of this second shell are oriented towards the non-polar groups of the outer shell, and the polar head groups are oriented towards the interior of the sphere. Such aggregates are called liposomes. In their structure, they resemble the lipid bilayer of the cell membrane. There are also multilayer liposomes in which at least two liposomal spheres are formed concentrically around each other, thus creating a multispherical aggregate. When administered in a lipophilic medium, these substances tend to form inverse spherical structures where the lipophilic chain is oriented toward the solution medium and the other layers are arranged accordingly.

Different uses of such charged spheres have been described in the art, including use as a dosage form for the application of lipophilic substances and/or to increase the bioavailability of the enclosed substance. In micelles, the closed non-polar substance is concentrated in the interior space of the sphere towards which the non-polar chains of the amphiphilic molecules are oriented. In liposomes, however, the interior space of the spheres is an aqueous medium, respectively hydrophilic. It can be used to package hydrophilic molecules. However, poorly water-soluble, respectively lipophilic, molecules gather mainly between the lipophilic structures of the liposomal layers.

Micelle-based solubilization techniques have been disclosed, for example, in WO 03/007907 A1 or WO 2014/094921 A1. An emulsifier with an HLB (hydrophilic-lipophilic balance) value of 9-16 or 13-18, respectively, is used there. Polysorbate (Tween) 20 or 80 is often used. The application of this technology is apparently limited to the production of chewing gum.

A solubilized luminol was disclosed by Shchipunov et al. (2008, Colloid J 70: 802-809) which consists of two surfactants, sodium dodecyl sulfate and alkyl polyglucoside to form micelles that surround the luminol. In this way luminol can be incorporated into a silicate hydrogel. Luminol can act inside as a biosensor.

Another approach is the addition of a glucuronidation inhibitor to the pharmaceutical composition. Surfactants such as poloxamers or polysorbate 20, polysorbate 60, polysorbate 80 are widely used. Another common inhibitor of glucuronidation is bioperine. However, glucuronidation inhibitors also inhibit the proper metabolization and, consequently, the elimination of other drugs or endogenous substances. Therefore, its use is a double-edged sword and must depend on the individual patient's medication. Therefore, this composition could pose problems for long-term medication, particularly in multimorbid patients.

From empirical pharmacokinetic measurements it is known that the body can absorb micelles and liposomes in the gastrointestinal tract through the intestinal villi. However, their extent of absorption appears to be quite variable and therefore these methods have had mixed success in increasing the bioavailability of the included compound. Transport, respectively, the rate of absorption across the cell membrane is an intrinsic characteristic of each substance that depends on various factors such as the size of the molecule, the degree of lipophilicity and the presence of suitable transport molecules within the cell membrane. For many compounds these parameters are not known and would have to be determined first before finding a suitable packaging for this specific compound.

Liposomal applications have been widely discussed in medicine and pharmacology and some sophisticated solutions have been developed for specific active agents. Its use, however, is not very common. One reason is the relatively high production costs, another reason is the possible adverse side effects. A liposome-based self-emulsification method for dietary supplements and poorly water-soluble pharmaceutically active agents was disclosed in EP 3290026 A1. In particular, when applied parenterally, liposomes carry the risk of accumulating in the liver, spleen and/or bone marrow. Therefore, liposomal formulations are often viewed with skepticism.

A nanoliposphere-based formulation method to increase the bioavailability of a drug was disclosed in WO 2013/108254. Although this method offers some advancement over the state of the art, it also has some inherent drawbacks. High-pressure homogenizers are needed for the production of these solid lipid nanoparticles. However, high pressure-induced drug degradation has been described for some drugs or dietary supplements. Lipid crystallization, gelation phenomena and coexistence of several colloidal species. Other restrictive factors, such as cytotoxic effects after phagocytosis, toxic effects of organic waste and difficult industrial scale-up have limited its use until now (Mehnert and Mader, Adv Drug Deliv Res 2001, 47, 165-196; Dudala et al., Int J Pharm Investg 2014, 4, 149-155). Furthermore, their drug loading capacity is relatively small and they have low viscosity. This makes them unattractive for forms of topical or transdermal application (Mukherjee et al., Indian J Pharm Sci 2009, 71, 349 358). Furthermore, WO 2013/108254 requires the use of an amphiphilic solvent such as lower alkyl esters of lactic acid or N-methylpyrrolidone. N-methylpyrrolidone is listed as a substance of very concern as it is potentially carcinogenic and toxic to reproduction; methyl lactate is usually hydrolyzed to lactate and methanol in an aqueous environment. Ethyl lactate etc. it is well tolerated.

However, due to relatively high production costs, it is not a very attractive solvent.

A solubilization technique for coenzyme Q ¹⁰ by means of light oil containing triglycerides was described in WO 03/007907 A1. Another solubilization technique for superior absorption of oxidized coenzyme Q ¹⁰ uses a lysolecithin, an oil and a fat in which the weight ratio of lysolecithin to coenzyme Q ¹⁰ is not less than 0.7 (US 2008/0145411 A1). Yet another coenzyme Q ¹⁰ solubilization technique uses vegetable oils or triglycerides, phospholipids such as hydroxylated lecithin in combination with a polysorbate surfactant such as polysorbate 80 (US 6,441,050 B1).

Another solubilization technique is the formation of inclusion complexes of the substance to be solubilized with cyclodextrins such as α-, β- or γ-cyclodextrin or cyclodextrin derivatives such as 2-hydroxypropyl-p-cyclodextrin, methyl-p-cyclodextrin or trimethyl-β. -cyclodextrin. Typically, cyclodextrins are composed of 6 to 8 linked 1,4-a-D-glucopyranosides that form macrocycles. Therefore, a water-soluble toroidal (coniform or cubiform) structure is generated that is capable of housing hydrophobic substances inside. The interior space is considerably less hydrophilic than the exterior in contact with the aqueous environment.

Cyclodextrins are produced from starch by enzymatic treatment. They are loaded with the compound to be solubilized by dispersion. The compound to be solubilized can then be released by contact of these complexes with water, by changes in pH or temperature, depending on the specific composition. However, the development of cyclodextrin is apparently not easy and relatively expensive. This limited its use until now. Another problem is that cyclodextrins interact with preservatives such as parabens.

Therefore, all these techniques have their advantages, but also some disadvantages.

Polysorbates are widely used in these solubilization techniques. However, there is ongoing controversy about the harmful health effects of polysorbates. Polysorbate 20 is disputed to be contaminated with 1,4-dioxane and unreacted ethylene oxide (at least from some suppliers). These are known carcinogenic substances permeable to the skin (cf. http://www.fda.gov/ohrms/dockets/98fr/060199a.txt, March 22, 2017). Polysorbate 80 was recently found to have detrimental effects on the murine gut microbiota, thereby promoting obesity and inflammatory bowel diseases (Chassaing et al., Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome, Nature, 2015, 519, 92-96). This is of particular importance for patients with chronic inflammatory bowel diseases (IBD) such as Crohn's disease (Roberts et al., Translocation of Crohn's disease Escherichia coli across M-cells: contrasting effects of soluble plant fibers and emulsifiers, Gut, 2010, 59, p. 1331-1339). IBD is a target indication for the therapeutic use of 5-amino-2,3-dihydrophthalazine-1,4-dione. Another problem with polysorbates such as Tween 80 is that they reduce the effectiveness of widely used preservatives such as parabens by binding them (see Blanchard et al., Effect of sorbitol on interaction of phenolic preservatives with polysorbate 80, 1977, J Pharm Sci 66, p. 1470-1473). However, the concentration of parabens should consequently not be increased due to its estrogenic potential (cf. Okubo et al., ER-dependent estrogenic activity of parabens assessed by proliferation of human breast cancer MCF-7 cells and expression of ERalpha and PR; 2001, Food Chem Toxicol 39, p. 1225-1232). Other well-known problems with polysorbates (particularly polysorbate 80) are hypersensitivity reactions in patients (see Steele et al., Hypersensitivity reactions to the polysorbate contained in recombinant erythropoietin and darbepoietin, Nephrology, 2005, 10, p. 317- 320; Norris et al., Polysorbate 80 hypersensitivity reactions: a renewed call to action, Commun Oncol, 2010, 7, 425-428). Polysorbate 80 has also been associated with systemic hypotension in amiodarone formulations where this can even lead to fatalities (cf. Cushing et al., PM 101: A cyclodextrin-based intravenous formulation of amiodarone devoid of adverse hemodynamic effects, Eur J Pharmacol, 2009 , 607, p. 167-172). A solubilization method for 5-amino-2,3-dihydrophthalazine-1,4-dione must meet the following criteria:

easy to handle

no long development time to find a favorable composition

no expensive equipment needed

economic materials and production costs

It is not necessary to add polysorbate solubilizers (Tween).

Surprisingly, it was found that the method according to the invention is capable of solving this task.

Description of the invention

Here, 5-amino-2,3-dihydrophthalazine-1,4-dione is solubilized by the method according to the invention, comprising the following steps:

a) Provide 5-amino-2,3-dihydrophthalazine-1,4-dione in the general range of 0.1% to 25% by weight at room temperature and a pressure of 0.2 bar to 1 bar;

b) Add the solubilization agents in any sequence.

at least one phosphatidylcholine in the total range of 20% to 80% by weight,

at least one medium chain triglyceride in the total range of 10% to 70% by weight,

at least one lysophosphatidylcholine in the total range of 1% to 15% by weight,

at least one C ² to C ⁴ alcohol in the total range of 1% to 20% by weight, and

at least one of glyceryl stearate and/or a saturated or unsaturated C ¹⁴ to C ²⁰ fatty acid in the total range of 0.5% to 10% by weight, respectively,

wherein the relative weight percentages of all ingredients add up to 100% and all solubilizing agents are pharmaceutically acceptable excipients;

c) Carefully heat the resulting mixture by continuously increasing the temperature with a continuous increase of 0.5 °C / min to 3 °C / min over a period of 20 to 60 minutes;

d) Stop the temperature increase in a temperature range of 30 °C to 125 °C as soon as a clear solution is reached; and

e) Let the resulting solubilized cool to room temperature.

In a preferred embodiment 5-amino-2,3-dihydrophthalazine-1,4-dione is solubilized by the method according to the invention, which comprises the following steps:

a) Provide 5-amino-2,3-dihydrophthalazine-1,4-dione in the general range of 0.5% to 10% by weight at room temperature and a pressure of 0.2 bar to 1 bar;

b) Add the solubilization agents in any sequence.

at least one phosphatidylcholine in the total range of 20% to 80% by weight,

at least one medium chain triglyceride in the total range of 10% to 70% by weight,

at least one lysophosphatidylcholine in the total range of 1% to 15% by weight,

at least one C ² to C ⁴ alcohol in the total range of 1% to 20% by weight, and

at least one of glyceryl stearate and/or a saturated or unsaturated C ¹⁴ to C ²⁰ fatty acid in the total range of 0.5% to 10% by weight, respectively,

wherein the relative weight percentages of all ingredients add up to 100% and all solubilizing agents are pharmaceutically acceptable excipients;

c) Carefully heat the resulting mixture by continuously increasing the temperature with a continuous increase of 0.5 °C / min to 3 °C / min over a period of 20 to 60 minutes;

d) Stop the temperature increase in a temperature range of 30 °C to 125 °C as soon as a clear solution is reached; and

e) Let the resulting solubilized cool to room temperature.

Another aspect of the invention is that the method according to the invention does not need polysorbates as solubilizers and/or emulsifiers. Therefore, 5-amino-2,3-dihydrophthalazine-1,4-dione can be solubilized by the method according to the invention, comprising the following steps:

a) Provide 5-amino-2,3-dihydrophthalazine-1,4-dione in the general range of 0.1% to 25% by weight at room temperature and a pressure of 0.2 bar to 1 bar;

b) Add the solubilization agents in any sequence.

at least one phosphatidylcholine in the total range of 20% to 80% by weight,

at least one medium chain triglyceride in the total range of 10% to 70% by weight,

at least one lysophosphatidylcholine in the total range of 1% to 15% by weight,

at least one C ² to C ⁴ alcohol in the total range of 1% to 20% by weight, and

at least one of glyceryl stearate and/or a saturated or unsaturated C ¹⁴ to C ²⁰ fatty acid in the total range of 0.5% to 10% by weight, respectively,

wherein the relative weight percentages of all ingredients add up to 100% and all solubilizing agents are pharmaceutically acceptable excipients;

c) Carefully heat the resulting mixture by continuously increasing the temperature with a continuous increase of 0.5 °C / min to 3 °C / min over a period of 20 to 60 minutes;

d) Stop the temperature increase in a temperature range of 30 °C to 125 °C as soon as a clear solution is reached; and

e) Let the resulting solubilized cool to room temperature,

characterized in that the resulting solubilized is devoid of polysorbate.

In additional embodiments, the solubilisates according to the invention can also be produced from salts of 5-amino-2,3-dihydrophthalazine-1,4-dione. Sodium, potassium and lithium salts have been described for therapeutic applications (see WO 2010/082858). Crystal structures for lithium, sodium, potassium, rubidium, and cesium salts have been described in Guzei et al. (2013, Journal of Coordination Chemistry 66, 3722-3739; see also WO 2011/107295 A1; WO 2016/96143 A1). In general, these salts are soluble in water and therefore do not need to be solubilized for aqueous solutions. However, when used therapeutically, solubilisates according to the invention are suitable for prolonging the shelf life of liquid dosage forms. In liquid dosage forms for oral administration they may mask the taste of solutions of the sodium salt 5-amino-2,3-dihydrophthalazine-1,4-dione which is unappealing to many patients. In addition, they improve the reabsorption of these 5-amino-2,3-dihydrophthalazine-1,4-dione salts from the gastrointestinal tract in terms of quantity and time. In this way bioavailability can be improved, which could lead to favorable pharmacokinetic properties. Larger ionic concentrations, however, hinder the formation of multilamellar vesicles which are considered essential for resolving the solubilisates according to the invention in an aqueous solution. Therefore, the maximum relative amounts of 5-amino-2,3-dihydrophthalazine-1,4-dione salts are lower than for the free base.

It was found that at most 2% by weight of the 5-amino-2,3-dihydrophthalazine-1,4-dione salts can be resolved according to the method of the invention.

Therefore, a salt of 5-amino-2,3-dihydrophthalazine-1,4-dione is solubilized by the method according to the invention, comprising the following steps:

a) Provide a salt of 5-amino-2,3-dihydrophthalazine-1,4-dione in the total range of 0.1% to 2% by weight at room temperature and a pressure of 0.2 bar to 1 bar,

wherein the salt is a sodium, potassium or lithium salt or mixtures thereof;

b) Add in any sequence the solubilizing agents of at least one phosphatidylcholine in the total range of 20% to 80% by weight,

at least one medium chain triglyceride in the total range of 10% to 70% by weight,

at least one lysophosphatidylcholine in the total range of 1% to 15% by weight,

at least one C2 to C4 alcohol in the total range of 1% to 20% by weight, and

at least one of glyceryl stearate and/or a saturated or unsaturated C14 to C20 fatty acid in the total range of 0.5% to 10% by weight, respectively,

wherein the relative weight percentages of all ingredients add up to 100% and all solubilizing agents are pharmaceutically acceptable excipients;

c) Carefully heat the resulting mixture by continuously increasing the temperature with a continuous increase of 0.5 °C / min to 3 °C / min over a period of 20 to 60 minutes;

d) Stop the temperature increase in a temperature range of 30 °C to 125 °C as soon as a clear solution is reached; and

e) Let the resulting solubilized cool to room temperature.

In preferred embodiments, also the embodiments of these 5-amino-2,3-dihydrophthalazine-1,4-dione salts are characterized in that the resulting solubilisate is devoid of polysorbate.

It is understood that the following descriptions and embodiments refer equally to said salts of 5-amino-2,3-dihydrophthalazine-1,4-dione such as to the free base.

Confusing and even contradictory definitions can be found in art. To avoid any ambiguity, a solubilisate according to the invention is defined as follows:

A solubilisate is the composition of 5-amino-2,3-dihydrophthalazine-1,4-dione or one of its salts or a mixture thereof and the solubilizing agents as defined according to the invention. The subsequent addition of a solvent or diluent will not be covered by this term. The solubilizer according to the invention is first produced by the solubilization method according to the invention, then a specific pharmaceutical composition is produced with said solubilizer, and finally said pharmaceutical composition is packaged in a pharmaceutically acceptable container appropriate for the respective dosage form.

The solubilizer according to the invention is characterized by the substantially complete solubilization of 5-amino-2,3-dihydrophthalazine-1,4-dione or one of its salts or a mixture thereof, therefore being an almost perfect solution in which molecules behave substantially as independent entities in a solution and are substantially subject to the distribution and thermodynamic rules of Brownian motion. Thus, the solubilized is a transparent solution containing 5-amino-2,3-dihydrophthalazine-1,4-dione or one of its salts or a mixture thereof in a high concentration. In general, the solubilisate is not intended for administration without dilution, respectively to be administered without being formulated in a pharmaceutically acceptable dosage form. In most cases, a portioned solubilisate represents a volume of a few ml.

Within the scope of this patent application, the terms "solubilizing aggregate" or "solubilizing essence" will be used synonymously with "solubilized." A solubilisate according to the invention must be differentiated from a suspension (colloidal suspension). This term defines a heterogeneous mixture containing solid particles that sooner or later undergo sedimentation. It is also different from an emulsion (a mixture of two liquids that are generally immiscible).

To increase the bioavailability of a substance, complete solubilization is highly preferable.

The term solubilized used according to the invention must be differentiated from the pharmaceutical composition. A pharmaceutical composition according to the invention is generated by diluting the solubilisate according to the invention in a preferably aqueous solution to produce a liquid dosage form, or by mixing the solubilisate into a topical dosage form, a capsule or a suppository.

A diluent in the scope of the present application is a diluent agent (diluting agent, solvent). It is not part of the solubilized according to the invention.

In the scope of the present application, the term "solubilizing agent" refers to any chemical substance that is added to 5-amino-2,3-dihydrophthalazine-1,4-dione or one of its salts or a mixture thereof. themselves to solubilize it so that 5-amino-2,3-dihydrophthalazine-1,4-dione or one of its salts or a mixture thereof can be resolved in an aqueous solution. The term "solubilizer" will be used synonymously.

In the scope of the present application, the term "medicine" includes human and veterinary medicine.

A great advantage of said solubilized is its small volume. Therefore, it can be easily divided into patient-friendly units, or relatively large quantities of solubilized substance can be shipped at low cost. To produce a dosage form, the preparation can be easily carried out by medical staff or patients.

The solubilized according to the invention must also be differentiated from a concentrate. A concentrate is a compound, respectively, a composition of compounds without diluent. When releasing a concentrate into a diluent, the concentrate dissolves completely in the diluent or forms a suspension or emulsion with the diluent. The concentrate does not need interaction with solubilizing agents, as it is intrinsically soluble in water or an aqueous solution.

In a preferred embodiment of the method according to the invention, 5-amino-2,3-dihydrophthalazine-1,4-dione is provided in the overall range of 2% to 15% by weight, in a more preferred embodiment in the range overall 2% to 10% by weight. Phosphatidylcholines are a class of choline-linked phospholipids. They are a main component of cell membranes and are obtained, for example, from egg yolk, ox liver, marine animals, krill oil or soybeans. In practice, it was shown that the origin of phosphatidylcholines considerably influences their biological and chemical effects. According to the invention, at least one phosphatidylcholine (PC) can be selected from the group comprising 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), natural (non-hydrogenated) or hydrogenated soy PC, Natural or hydrogenated egg PC, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) or 1,2-dioleoyl-sn-glycero -3-phosphocholine (DOPC), 1-oleoyl-palmitoyl-phosphocholine (OPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), mono-stearoyl-sn-phosphocholine (MSPC), di-arachidoyl -snphosphocholine (DAPC) and its mixtures. Preferred phosphatidylcholines are non-hydrogenated soy PC, DMPC, POPC and DOPC. Non-hydrogenated phosphatidylcholines are also preferred. Particularly preferred is non-hydrogenated soy PC.

For topical dosage forms of a solubilisate according to the invention, non-hydrogenated phosphatidylcholines are particularly preferred.

Lecithin is commonly used synonymously with phosphatidylcholines. It is a mixture of phosphatidylcholine and other compounds.

According to the method of the invention, phosphatidylcholines are used in the overall range of 20% to 80% by weight, preferably 40% to 70% by weight, more preferably 50% to 65% by weight and most preferred 60% by weight.

Medium chain triglycerides (MCTs) refer to triglycerides whose fatty acids have an aliphatic tail of 6 to 12 carbon atoms. The fatty acids incorporated in MCTs are called medium chain fatty acids. (AGCM). In triglycerides, three fatty acid molecules are linked to a glycerol backbone. By definition, in MCTs at least two of these three fatty acids must be MCFAs. According to the invention, the MCFAs can be selected independently of each other from the group comprising caproic acid, enantic acid, caprylic acid, pelargonic acid, capric acid, undecylicic acid, lauric acid, their unsaturated derivatives and mixtures thereof. Preferred MCFAs are caproic acid, caprylic acid, capric acid and lauric acid.

It may be advantageous in some embodiments of the invention to use triglycerides containing 1 to 3 residues of myristic acid and/or palmitic acid instead of MCFA. Therefore, these two fatty acids will also be subsumed under the term MCT according to the invention.

MCT oils or MCT greases are oils or greases that predominantly contain MCTs. These terms refer to a respective mixture of different TCMs that may contain a variety of MCFAs. According to the invention, any reasonable mixing ratio will be covered by these terms. MCT fats are often extracted from specific vegetable fats, while MCT oils do not occur naturally. MCT oils and MCT fats are widely marketed as a healthy dietary supplement, respectively as a substitute for long-chain fats in nutrition.

According to the method of the invention, the TCMs are used in an overall range of 10% to 70% by weight, preferably 20% to 40% by weight, more preferably 25% to 35% by weight and most preferred of 30% by weight.

Lysophosphatidylcholines (LPC, lysoPC, also: lysolecithins) are a class of phosphatidylcholine derivatives, resulting from their partial hydrolysis in which one of the fatty acid groups is removed. In the body, this hydrolysis is carried out by the enzyme phospholipase A2. According to the invention, at least one lysophosphatidylcholine can be selected independently of each other from the group comprising all hydrolyzed compounds of the phosphatidylcholines listed above, 1 -lysophosphatidylcholines (2-acyl-sn-glycero-3-phosphocholines), 2 -lysophosphatidylcholines, L-alpha-lysophosphatidylcholine, and their mixtures.

According to the method of the invention, lysophosphatidylcholines are used in the overall range of 1% to 15% by weight, preferred 3% to 8% by weight, more preferred 5% to 7% by weight and most preferred 6% by weight.

Within the scope of the present application, said lysophosphatidylcholines are not a mere variant or substitute of phosphatidylcholines but perform an independent function. Surprisingly, it was found that two solubilizing agents of similar but not identical chemical constitution can significantly improve the solubilizing effect, if used in an unequal proportion. According to the invention, the ratio of phosphatidylcholine to lysophosphatidylcholine is from 80:1 to 1.33:1, preferred from 40:1 to 3:1, more preferred from 25:1 to 5:1 and most preferred from 20:1 to 5:1. :1 to 8:1.

According to the invention, at least one C2 to C4 alcohol (lower alcohol) can be selected from the group comprising ethanol, propanol, isopropanol, butan-1-ol, butan-2-ol, isobutanol (2-methyl-1- propanol), ethylene glycol (ethane-1,2-diol), a -propylene glycol (propane-1,2-diol), p-propylene glycol (propane-1-3-diol), 1,2-butylene glycol (butane-1, 2-diol), 1,3-butylene glycol (butane-1,3-diol), 1,4-butylene glycol (butane-1,4-diol) and diethylene glycol. Ethanol is preferred.

According to the method of the invention, C2 to C4 alcohols are used in the overall range of 1% to 20% by weight, preferred 2% to 10% by weight, more preferred 3% to 8% by weight and most preferred 5% by weight.

Glyceryl stearate (glycerol monostearate, MEG) is an emulsifier. The flaky powder is also hygroscopic. MEG is used as a thickener, emulsifier, anti-caking agent, anti-blocking agent and preservative. According to the invention, at least one saturated or unsaturated C14 to C20 fatty acid can be used instead of or in combination with glyceryl stearate. It can be selected from the group comprising myristic acid (14:0), pentadecanoic acid (15:0), palmitic acid (16:0), heptadecanoic acid (17:0), stearic acid (18:0), nonadecanoic acid (19:0), arachidic acid (20:0), myristoleic acid (14:1, cis-A ⁹ ), palmitoleic acid (16:1, cis-A ⁹ ), sapienic acid (16:1, cis-A ⁶ ), hexadecatrienoic acid (16:3, (n-3), oleic acid (18:1, cis-A ⁹ ), elaidic acid (18:1, trans-A ⁹ ), vaccenic acid (18:1, trans -A ¹¹ ), linoleic acid (18:2; cis,cis-A ⁹ ,A ¹² ), linoleadic acid (18:2, trans,trans-A ⁹ , A ¹² ), a -linolenic acid (18:3, cis,cis,cis-A ⁹ ,A ¹² ,A ¹⁵ ), y-linolenic acid (18:3, (ro-3)), calendic acid (8E,10E,12Z-octadecatrienoic acid), stearidonic acid (18: 4 (n-3)), dihomo-y-linolenic acid (20:3; (ro-6)), eicosadienoic acid (20:2, (n-6)), eicosatrienoic acid (20:3, (n- 3)), eicosatetraenoic acid (20:4, (n-3)), arachidonic acid (20:4, cis,cis,cis,cis-A ⁵ ,A 8,A ^{11 ,} A ¹⁴ ), eicosapentaenoic acid (20 :5, cis,cis,cis,cis,cis-A ⁵ ,A ⁸ ,A ¹¹ ,A ¹⁴ ,A ¹⁷ ).

Even numbered C14 to C20 fatty acids are preferred. Particularly preferred is oleic acid.

According to the method of the invention, glyceryl stearate and/or a saturated or unsaturated C14 to C20 fatty acid are used in the overall range of 0.5% to 10% by weight, preferred 1% to 8% by weight, more preferred 2% to 6% by weight and most preferred 3% by weight.

The method according to the invention is usually started at room temperature. However, in alternative embodiments it could also be possible to preheat 5-amino-2,3-dihydrophthalazine-1,4-dione and/or any of the solubilizing agents to be added in step b) of the method of the invention, provided that the Preheating temperature does not exceed 28 °C.

The method according to the invention can be carried out at a pressure of 0.2 bar to 1 bar. However, it is preferred to run the method at 1 bar (atmospheric pressure). For certain applications, it may be preferable to use a light vacuum. The technical equipment for applying, maintaining and controlling said light vacuum is well known in the art.

According to the method of the invention, the resulting mixture is carefully heated in step c) by continuously increasing the temperature over a period of 20-60 minutes. In preferred embodiments, this period is 25 to 40 minutes, and most preferred 30 to 35 minutes.

An essential feature of the method according to the invention is temperature control (temperature increase by time and duration of heating). While there is variability in the relative amounts of solubilizing agents, controlled temperature increases are essential. Apparently, there is an optimal window for each substance to be solubilized, depending on the mixture of solubilizing agents used. Exact values are difficult to predict, they have to be found empirically. The continuous temperature increase (the slope of the temperature ramp) can vary between 0.5 °C/min to 3 °C/min, preferred 1 °C/min to 2 °C/min and most preferred 2 °C /min.

According to step d) the temperature rise is stopped in a temperature range of 30 °C to 125 °C as soon as a transparent solution is reached. This moment largely depends on the selected solubilizing agents and reaction conditions. Apparently, it is not possible to predict this "solubilization temperature" based on the specific components to be used. Each composition of these components shows specific characteristics that must be discovered experimentally. Therefore, the experimenter has to find the optimal combination of these parameters.

It is understood that the method according to the invention can be varied such that any of the solubilizing agents of step b) can be provided first and then 5-amino-2,3-dihydrophthalazine-1,4-dione or one of its salts or a mixture thereof, as well as the other solubilizing agents, can be added in any sequence. It is also possible to provide a mixture of the solubilizing agents of step b) first and then add 5-amino-2,3-dihydrophthalazine-1,4-dione or one of its salts or a mixture thereof. This variation was found to be neutral for the result of the method according to the invention.

In a preferred embodiment, said mixture of the solubilizing agents of step b) and 5-amino-2,3-dihydrophthalazine-1,4-dione or one of its salts or a mixture thereof is provided in a system with two compartments. This can facilitate the solubilization process according to the invention and each compartment can be marketed separately. This may be advantageous for the stability and therefore the shelf life of the dosage form according to the invention.

The time at which the resulting solubilisate has become a clear solution is determined by observation of the experimenter. In general, this moment is achieved when the solution appears clear and does not show sedimentation, precipitation, ligations, spots or streaks (zebra effect).

In an alternative embodiment, the parameters for the temperature ramp according to the invention that have been determined as described above can be implemented in an automated or semi-automated device configuration. This can be advantageous, for example, in a high-end industrial application.

Solubilisates produced in accordance with the method of the invention maintain this clarity upon cooling and remain clear and stable upon storage. The achievable storage time of a pharmaceutical dosage form containing such a solubilisate (which approximately corresponds to the shelf life of a product) is apparently not limited. In preliminary stability analyses, the minimum storage time was never less than 6 months. However, to increase the shelf life of these solubilized 5-amino-2,3-dihydrophthalazine-1,4-dione or one of its salts or a mixture thereof, at least one antioxidant can be added to the solubilized . In preferred embodiments, this at least one antioxidant is a pharmaceutically acceptable excipient. Appropriate antioxidants may be selected from the group comprising lactic acid, ascorbic acid, sodium ascorbate, calcium ascorbate, potassium ascorbate, fatty acid esters of ascorbic acid, ascorbyl palmitate, ascorbyl stearate, tocopherols, alpha-tocopherol, beta -tocopherol, gammatocopherol, delta-tocopherol, alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol, delta-tocotrienol, propyl gallate, octyl gallate, dodecyl gallate, ethyl gallate, guaiac resin, erythorbic acid, erythorbate sodium, erythorbine acid, erythorbine sodium, terbutyl hydroquinone, butylhydroxyanisole, butylhydroxytoluene, mono-, di-, trisodium phosphate, mono-, di-, tripotassium phosphate, anoxomer, ethoxyquin, potassium lactate, stannous chloride, sodium thiosulfate , 4-hexylresorcinol, glucose oxidase.

Ascorbyl palmitate and alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol are preferred. Particularly Preferred is a combination of ascorbyl palmitate and at least one of alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol.

The term tocopherol(s) refers to any of the aforementioned tocopherols or a mixture thereof.

According to the method of the invention, this at least one antioxidant can be optionally added to said solubilized or its preferred embodiments in the overall range of 0.01% to 10% by weight, preferred from 0.1% to 5% by weight. , more preferred 0.2% to 1% by weight and most preferred 0.3% to 0.5% by weight.

Therefore, the present application also refers to a solubilisate resulting from the solubilization method according to the invention:

A solubilized of 5-amino-2,3-dihydrophthalazine-1,4-dione comprising 5-amino-2,3-dihydrophthalazine-1,4-dione provided in the range of 0.5% to 10% by weight at ambient temperature and a pressure of 0.2 bar to 1 bar, at least one phosphatidylcholine in the overall range of 20% to 80% by weight;

at least one medium chain triglyceride in the overall range of 10% to 70% by weight;

at least one lysophosphatidylcholine in the overall range of 1% to 15% by weight;

at least one C ² to C ⁴ alcohol in the overall range of 1% to 20% by weight, and

and at least one of glyceryl stearate or a saturated or unsaturated C ¹⁴ to C ²⁰ fatty acid in the range of 0.5% to 10% by weight, respectively,

wherein the relative percentages by weight of all ingredients add up to 100% and all solubilizing agents are independently of each other a food additive or pharmaceutically acceptable excipients and the solubilisate is free of polysorbate.

In a preferred embodiment, the solubilisate according to the invention comprises 5-amino-2,3-dihydrophthalazine-1,4-dione in the range of 1% to 8% by weight and

a) at least one phosphatidylcholine in the overall range of 40% to 70% by weight;

b) at least one medium chain triglyceride in the overall range of 20% to 40% by weight;

c) at least one lysophosphatidylcholine in the overall range of 3% to 8% by weight;

d) at least one C ² to C ⁴ alcohol in the overall range of 2% to 10% by weight, and

e) and at least one of glyceryl stearate or a saturated or unsaturated C ¹⁴ to C ²⁰ fatty acid in the range of 0.5% to 5% by weight respectively,

wherein the relative percentages by weight of all ingredients add up to 100% and all solubilizing agents are independently of each other pharmaceutically acceptable excipients.

In another preferred embodiment, the solubilized according to the invention comprises 5-amino-2,3-dihydrophthalazine-1,4-dione in a range of 2% to 5% by weight and

a) at least one phosphatidylcholine in the overall range of 40% to 60% by weight;

b) at least one medium chain triglyceride in the overall range of 25% to 35% by weight;

c) at least one lysophosphatidylcholine in the overall range of 5% to 7% by weight;

d) at least one C ² to C ⁴ alcohol in the overall range of 4% to 7% by weight, and

e) and at least one of glyceryl stearate or a saturated or unsaturated C ¹⁴ to C ²⁰ fatty acid in the range of 0.5% to 5% by weight, respectively,

wherein the relative percentages by weight of all ingredients add up to 100% and all solubilizing agents are independently of each other pharmaceutically acceptable excipients.

In alternative embodiments, the method according to the invention also relates to:

A solubilizer comprising a salt of 5-amino-2,3-dihydrophthalazine-1,4-dione in the range of 0.1% to 2% by weight and the following solubilizing agents,

wherein said salt is a sodium, potassium or lithium salt or a mixture thereof, and

a) at least one phosphatidylcholine in the overall range of 20% to 80% by weight;

b) at least one medium chain triglyceride in the overall range of 10% to 70% by weight;

c) at least one lysophosphatidylcholine in the overall range of 1% to 15% by weight;

d) at least one C ² to C ⁴ alcohol in the overall range of 1% to 20% by weight, and

e) and at least one of glyceryl stearate or a saturated or unsaturated C ¹⁴ to C ²⁰ fatty acid in the range of 0.5% to 10% by weight, respectively,

wherein the relative percentages by weight of all ingredients add up to 100% and all solubilizing agents are independently of each other pharmaceutically acceptable excipients.

According to the invention, said solubilized or its preferred embodiments may additionally contain an antioxidant as listed above in the overall range of 0.01% to 10% by weight, preferred 0.1% to 5% by weight, more preferred 0.2% to 1% by weight and most preferred 0.3% to 0.5% by weight.

In a particularly preferred embodiment of this solubilisate, said at least one C14 to C20 saturated or unsaturated fatty acid is oleic acid.

In a particularly preferred embodiment of this solubilisate, said at least one C2 to C4 alcohol is ethanol.

In preferred embodiments, at least one antioxidant in the overall range of 0.01 to 10% by weight is additionally contained in the solubilisate according to the invention, wherein said at least one antioxidant is a pharmaceutically acceptable excipient.

In particularly preferred embodiments, said at least one antioxidant is ascorbyl palmitate and/or at least one tocopherol.

Another aspect of the present application is a solubilized according to the invention for prophylactic or therapeutic use in medicine, as well as the prophylactic or therapeutic use of said solubilized in medicine.

Within the scope of this application, the term "medicine" shall refer to both human and veterinary medicine.

In particular, the present application refers to the solubilisate according to the invention for prophylactic or therapeutic use as an immunomodulator.

The present application also relates to the use of a solubilisate according to the invention to treat conditions with an exaggerated immune reaction or conditions with an immunodeficient background.

The present application also relates to a pharmaceutical composition for treating a medical condition, comprising a solubilized according to the invention of 5-amino-2,3-dihydrophthalazine-1,4-dione or one of its salts or a mixture of the same.

Here the term permeability refers to the degree of absorption of a drug in humans through the intestinal wall. According to the established definition, a drug is classified as highly permeable if 90% or more of the orally administered dose is reabsorbed in the gastrointestinal tract. Consequently, a drug that has an absorption rate of less than 90% is classified as low permeability.

Therefore, solubility and permeability are intrinsic properties of the substance. Absorption and bioavailability, however, describe pharmaceutical parameters that can be improved with appropriate measures. While absorption refers to the fraction of the amount of orally applied substance that is absorbed from the gastrointestinal tract, the bioavailability of a substance depends not only on absorption but also on the binding of species-specific proteins in the blood. and pharmacokinetic parameters such as first-pass metabolism.

Therefore, another aspect of the invention is the prophylactic or therapeutic use of a solubilisate according to the invention to improve the absorption and/or bioavailability of 5-amino-2,3-dihydrophthalazine-1,4-dione or one of its salts or a mixture thereof.

Therefore, the present application also relates to a solubilisate according to the invention for use in a pharmaceutical dosage form.

Furthermore, the present application also relates to the use in medicine of the solubilisate according to the invention in a pharmaceutical dosage form.

In most cases, the solubilization of 5-amino-2,3-dihydrophthalazine-1,4-dione or one of its salts or a mixture thereof is not yet a pharmaceutical dosage form. To be ready for ingestion in a liquid dosage form, such a solubilisate must be resolved in a diluent. The preferred diluent for liquid dosage forms is water. Therefore, the solubilisate according to the invention is added to an aqueous solution in a suitable container. The container may be selected from a group comprising, but not limited to, bottles, vials, jars, glasses, cups, syringes, jars, pots, dispensers, boxes, tubes, lids, sachets, and custom two- or multi-compartment containers. Preferred containers are bottles, vials, jars.

It is preferred that the container with the aqueous solution and the solubilized resolved therein be stirred or shaken several times to ensure a homogeneous distribution of the solubilized in the aqueous solution.

Therefore, the present application also relates to a pharmaceutical dosage form, in which a solubilisate according to the invention is resolved into an aqueous solution.

In another preferred embodiment of the invention, a solubilisate according to the invention is included in soft gelatin capsules (CGB). CGBs dissolve as they pass through the gastrointestinal tract. They consist mainly of gelatin enriched with varying amounts of plasticizers such as glycerol or sorbitan. The release rate depends on the specific formulation of the CGB carrier material. They are also suitable for sustained release of the active agent. CGBs are particularly useful for the administration of active agents that are poorly soluble in water. They are excellent for housing a solubilized 5-amino-2,3-dihydrophthalazine-1,4-dione in a cavity.

In another embodiment of the invention, a solubilisate according to the invention is provided in hard gelatin capsules. They consist of gelatin, water and usually a colorant, but do not contain a plasticizer. A solubilisate according to the invention can be included during the production process. It will be released upon dissolution of the hard gelatin capsule.

In another preferred embodiment of the invention, a solubilisate according to the invention is included in chewable tablets or hard candies. Here the solubilized according to the invention is integrated into the matrix of the tablets or candies.

In a further embodiment of the invention, a solubilisate according to the invention is included in a suppository. In a typical production method, waxes with a low melting point, as well as a mixture of fatty acid glycerides such as cocoa butter, are melted first. Then, the active agent, here a solubilized of 5-amino-2,3-dihydrophthalazine-1,4-dione or one of its salts or a mixture thereof, is homogeneously dispersed under stirring or other mixing methods. The molten homogeneous mixture is then transferred to appropriate molds and cooled until solidification.

In yet another embodiment of the invention, a solubilisate according to the invention is provided as a form of topical application, such as creams, emulsions, lotions, gels, hydrogels, pastes, powders, ointments, liniments, films, liposomes, dermal patches, patches. transdermals, transdermal sprays or suspensions.

In another aspect, the present application also relates to a pharmaceutical composition containing 5-amino-2,3-dihydrophthalazine-1,4-dione or a salt thereof or a mixture thereof formulated in a dosage form as defined above, and at least one pharmaceutically acceptable excipient.

The term "pharmaceutical excipients" refers to natural or synthetic compounds that are added to a pharmaceutical formulation along with the pharmaceutically active agent. They can contribute to increasing the volume of the formulation, improving the desired pharmacokinetic properties or stability of the formulation, as well as being beneficial in the manufacturing process.

Advantageous classes of excipients according to the invention include vehicles, binders, lubricants, glidants, disintegrants, colorants, buffers, preservatives, emulsifiers, permeation enhancers, antioxidants, diluents, pH adjusters, fatteners, solvents, viscorizants, hydrotropics, sweeteners, acidulants , thickeners, non-stick agents, fillers, flavorings, sweeteners, opacifiers, flavorings and aromatic substances. It may be advantageous, respectively mandatory, to add one or more pharmaceutically acceptable carriers to a pharmaceutically active agent. All vehicles known in the art and their combinations are admissible. In solid dosage forms they can be, for example, vegetable and animal fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, zinc oxide. For liquid dosage forms and emulsifiers, suitable vehicles are, for example, solvents, solubilizers, emulsifiers such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol, oil cottonseed, peanut oil, olive oil, castor oil, sesame oil, glycerol fatty acid esters, polyethyl glycols, sorbitan fatty acid esters. Suspensions according to the invention may contain vehicles conventionally known as diluents (e.g. water, ethanol or propylene glycol), ethoxylated isostearyl alcohols, polyoxyethylene and polyoxyethylene sorbitan esters, microcrystalline celluloses, bentonites, agar, tragacanth.

The term binders refers to substances that bind gunpowders or glue them together, rendering them cohesive through the formation of granules. They serve as the “glue” of the preparation. Binders increase the cohesive strength of the provided diluent or filler.

Suitable binders are wheat, corn, rice or potato starch, gelatin, carbohydrate substances such as glucose, sucrose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or calcium ammonium alginate, sodium alginate , carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropylcarboxymethyl cellulose, polyethylene glycol, polyvinylpyrrolidone, magnesium-aluminum silicate, waxes and others. The percentage of the binder in the composition can vary between 1 - 30% by weight, preferably 2 - 20% by weight, particularly preferred 3 - 10% by weight and most preferred 3 - 6% by weight.

Colorants are excipients that lend color to the composition or galenic form. They can be food coloring. They may also be adsorbed on an appropriate adsorption agent such as clay or aluminum oxide. The amount of the dye can vary between 0.01 and 10% by weight of the composition, preferably between 0.05 and 6% by weight, particularly preferred between 0.1 and 4% by weight, most preferred between 0.1 and 1% by weight.

Appropriate food colors are curcumin, riboflavin, riboflavin 5'-phosphate, tartrazine, alkanine, quinoline yellow WS, AB yellow, riboflavin sodium 5'-phosphate, yellow 2G, twilight yellow, E111 orange, carmine, citrus red 2, azorubine, amaranth, cochineal red A, Ponceau SX, Ponceau 6R, erythrosine, red 2G, allura red AC, indantrene, patent blue V, indigotin I, brilliant blue FCP, chlorophylls and chlorophyllins, copper complexes of chlorophylls and chlorophyllins, green bright acid BS, fast green FCF, ordinary candy, caustic sulfite candy, ammonia candy, ammonium sulfite candy, bright black BN, soot, charcoal, FK brown, HT chocolate brown, alpha-carotene, beta-carotene, gamma -carotene, annatto, bixin, norbixin, paprika extract, capsanthin, capsorubin, lycopene, apocarotinal 8', apocarotenic acid-8' ethyl ester, flavoxanthin, lutein, cryptoxanthin, rubixanthin, violaxanthin, rhodoxanthin, canthaxanthin, zeaxanthin, citranaxanthin , astaxanthin, betanin, anthocyanins, saffron, calcium carbonate, titanium dioxide, ferrous oxides, ferrous hydroxides, aluminum, silver, gold, lithol-rubin BK, tannic acid, orcein, iron gluconate and iron lactate.

Furthermore, buffers or buffer solutions for liquid dosage forms are preferred, particularly for pharmaceutical liquid dosage forms. The terms buffer, buffer system and buffer solution refer to the ability of a system, especially an aqueous solution, to resist a change in pH by addition of acid or base or by dilution with a solvent. Preferred buffer systems may be selected from the group comprising formate, lactate, benzoic acid, oxalate, fumarate, aniline, acetate buffer, citrate buffer, glutamate buffer, phosphate buffer, succinate, pyridine, phthalate, histidine, MES (acid 2-morpholino ethanesulfonic acid), maleic acid, cacodylate buffer (dimethyl arsenate), carbonic acid, ADA (N-(2-acetamido) iminodiacetic acid), PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid), BIS-TRIS-propane buffer (1,3-bis[tris(hydroxymethyl)methylamino]propane), ethylenediamine, ACES (2-[(2-amino-2-oxoethyl)amino]ethanesulfonic acid), imidazole, MOPS (3 - (N-morphino)propanesulfonic acid), diethyl malonic acid, TES (2-[tris(hydroxymethyl)methyl]aminoethanesulfonic acid), HEPES (N-2-hydroxyethyl-piperazine-N'-2-ethanesulfonic acid buffer) as well as plus buffers with a pKa between 3.8 and 7.7.

Preferred are carbonic acid buffers such as acetate and dicarbonic acid buffers such as fumarate, tartrate and phthalate as well as tricarbonic acid buffers such as citrate.

Another group of preferred buffers are inorganic buffers such as sulfate hydroxide, borate hydroxide, carbonate hydroxide, oxalate hydroxide, calcium hydroxide and phosphate buffers. Another group of preferred buffers are nitrogen buffers such as imidazole diethyldiamine and piperazine. Furthermore, sulfonic acid buffers such as TES, HEPES, ACES, PIPES, 3-[tris-(hydroxymethyl)methylamino]-propanesulfonic acid (TAPS), 4-(2-hydroxyethyl)piperazine-1-propanesulfonic acid (EEPS) are preferred. , 3-(N-morphino)propanesulfonic acid (MOPS) and N,N'-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES). Another group of preferred buffers are glycine, glycylglycine, glycyl-glycylglycine, N,N'-bis(2-hydroxyethyl) glycine and N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl] glycine (tricine). Also preferred are amino acid buffers such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophan, lysine, arginine, histidine, aspartate, glutamate, asparagine, glutamine, cysteine, methionine, proline, 4- hydroxyproline, N,N,N-trimethyl lysine, 3-methylhistidine, 5-hydroxylysine, o-phosphoserine, [gamma]-carboxyglutamate, [epsilon]-N-acetyl lysine, [omega]-N-methyl arginine, citrulline, ornithine and its derivatives.

Preservatives for liquid pharmaceutical forms can be added if necessary. They can be selected from the group comprising sorbic acid, potassium sorbate, calcium sorbate, methylparaben, ethylparaben, methyl-ethylparaben, propylparaben, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, heptyl p-hydroxybenzoate, methyl-p-hydroxybenzoate sodium, sodium ethyl-p-hydroxybenzoate, sodium propyl-p-hydroxybenzoate, benzyl alcohol, benzalkonium chloride, phenylethyl alcohols, cresols, cetylpyridinium chloride, chlorobutanol, thiomersal (sodium mercurothiosalicylate), sulfur dioxide, sodium sulfite, bisulfite sodium, sodium metabisulfite, potassium metabisulfite, potassium sulfite, calcium sulfite, calcium hydrogen sulfite, potassium hydrogen sulfite, biphenyl, orthophenyl phenol, sodium orthophenyl phenol, thiabendazole, nisin, natamycin, formic acid, sodium formate , calcium formate, hexamine, formaldehyde, dimethyl dicarbonate, potassium nitrite, sodium nitrite, sodium nitrate, potassium nitrate, acetic acid, potassium acetate, sodium acetate, sodium diacetate, calcium acetate, acetate ammonium, dehydroacetic acid, sodium dehydroacetate, lactic acid, propionic acid, sodium propionate, calcium propionate, potassium propionate, boric acid, sodium tetraborate, carbon dioxide, malic acid, fumaric acid, lysozyme, copper sulfate ( II), chlorine, chlorine dioxide and other appropriate substances or compositions known to those skilled in the art.

Additional emulsifiers can be selected from the following anionic and nonionic emulsifiers: anionic emulsifying waxes, cetyl alcohol, cetostearyl alcohol, stearic acid, oleic acid, polyoxyethylene/polyoxypropylene block copolymer, additional product from 2 to 60 mol of ethylene oxide to oil castor and/or tempered castor oil, lanolin, sorbitan esters, polyoxyethylene alkyl esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, monopalmitate polyoxyethylene sorbitan, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polyoxyethylene stearate, polyvinyl alcohol, metatartaric acid, calcium tartrate, alginic acid, sodium alginate, potassium alginate, ammonium alginate, calcium alginate, alginate propane-1,2-diol, carrageenan, processed eucheuma algae, locust bean gum, tragacanth, acacia gum, karaya gum, gellan gum, gati gum, glucomannan, pectin, pectin amidata, ammonium phosphatides, brominated vegetable oil , sucrose acetate isobutyrate, glyceride esters of rosin, disodium phosphate, trisodium diphosphate, tetrasodium diphosphate, dicalcium diphosphate, calcium dihydrogen diphosphate, sodium trisphosphate, pentapotassium triphosphate, sodium polyphosphates, sodium calcium polyphosphate, calcium polyphosphates, polyphosphate ammonium, beta-cyclodextrin, pulverized cellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropyl-methylcellulose, ethyl-methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethyl-hydroxyethylcellulose, croscarmellose, enzymatically hydrolyzed carboxymethylcellulose, mono- and diglycerides of fatty acids, monostearate glyceryl, glyceryl distearate, acetic acid esters of mono- and diglycerides of fatty acids, lactic acid esters of mono- and diglycerides of fatty acids, citric acid esters of mono- and diglycerides of fatty acids, tartaric acid esters of mono- and diglycerides of fatty acids, mono- and diacetyltartaric acid esters of mono- and diglycerides of fatty acids, mixed acetic acid and tartaric acid esters of mono- and diglycerides of fatty acids, sucinylated monoglycerides, fatty acid esters of sucrose, sucroglycerides, polyglycerol fatty acid esters, polyglycerol polyricinoleate, propane-1,2-diol fatty acid esters, polypropylene glycol fatty acid esters, propane-1 glycerol fatty acid esters lactylate, thermally modified soybean oil oxidized interacted with mono- and diglycerides of fatty acids, sodium dioctylsulfosucinate, sodium stearoyl-2-lactylate, calcium stearoyl-2-lactylate, stearyl tartrate, stearyl citrate, sodium stearyl fumarate, calcium stearyl fumarate, sodium lauryl sulfate , ethoxylated mono- and diglycerides, coconut oil ester methylglucoside, sorbitan monostearate, sorbitan tristearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan trioleate, calcium sodium polyphosphate, calcium polyphosphate, polyphosphate ammonium, cholic acid, choline salts, distarch glycerol, sodium starch octenylsucinate, acetyl oxidized starch.

Glycerol monooleate and stearic acid are preferred.

Stabilizers are substances that can be added to prevent unwanted changes. Although stabilizers are not true emulsifiers, they can also contribute to the stability of emulsions, respectively solubilized. Suitable examples for stabilizers are oxystearin, xanthan gum, agar, oat gum, guar gum, tara gum, polyoxyethylene stearate, aspartame and acesulfame salt, amylase, proteases, papain, bromelain, ficin, invertase, polydextrose, polyvinylpyrrolidone, Polypyrrolidone polyvinyl, triethyl citrate, maltitol, maltitol syrup.

Suitable as solubilizers additional surfactants (solubilizers) are, for example, diethylene glycol monoethyl ester, copolymers of polyethylene glycol and propylene glycol, cyclodextrins such as a- and p-cyclodextrin, glyceryl monostearates such as Solutol HS 15 (Macrogol-15-hydroxystearate from BASF, PEG 660-15 hydroxystearates), sorbitan esters, polyoxyethylene glycol, polyoxyethylene sorbitan acid esters, polyoxyethylene sorbitan monooleate, polyoxyethylene oxystearic acid triglyceride, polyvinyl alcohol, sodium dodecyl sulfate, glyceryl monooleates (anionic), etc.

Additional appropriate solvents may be selected from the group comprising, but not limited to, water, carbonated water, water for injection, water with isotonizing agents, saline, isotonic saline, alcohols, particularly ethyl and n-butyl alcohol, glycols, triglycerides of oleic and linoleic acids, mono-, di- and triglycerides of caprylic and capric acid, glycerides of capric and caprylic acid of polyoxyethylene, fatty acid esters of propylene glycol, low alkyl fatty acid esters, soybean oil , propylene glycol laurate, polyoxyethylene castor oil (35), polyoxyethylene glyceryltrioleate, ethyl butyrate, ethyl caprylate, ethyl oleate and their mixtures.

Suitable isotonizing agents are, for example, pharmaceutically acceptable salts, in particular sodium chloride and potassium chloride, sugars such as glucose or lactose, sugar alcohols such as mannitol and sorbitol, citrate, phosphate, borate and mixtures thereof.

Appropriate thickening agents may be selected from the group comprising, but not limited to, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, dextrins, polydextrose and modified starch.

Diluents or fillers are inactive substances added to drugs to handle minimal amounts of active agents. They can be useful in the solubilization process. Examples of suitable diluents are water, mannitol, pregelatinized starch, starch, microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate dihydrate, calcium phosphate, calcium carbonate, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol, xanthan gum, gum arabic. or any combination thereof.

Penetration enhancers are frequently used in topical dosage forms. Suitable penetration enhancers comprise all pharmaceutically acceptable penetration enhancers known in the art. prior art, such as, but not limited to, azones such as lauro-caprama, 1-dodecylazocyclo-heptane-2-one; sulfoxides such as dimethyl sulfoxide, DMAC, DMF; pyrrolidones such as 2-pyrrolidone, N-methyl-2-pyrrolidone; alcohols such as ethanol, propane-1,2-diol or decanol; glycols such as propylene glycol, diethylene glycol, tetraethylene glycol; fatty acids such as oleic acid, lauric acid, sodium dodecyl sulfate, myristic acid, isopropylmyristic acid, capric acid; nonic surfactants such as polyoxyethylene 2-oleic ether, polyoxyethylene 2-stearic ether; terpenes; terpenoids; oxazolidinones; urea; ceramide analogues, azone analogues, menthol derivatives, etherified derivatives, esterified derivatives, trans-carbamates, carbamatic salts, TXA derivatives, DDAIP (dodecyl-2-dimethylamino-propanoate), DDAK, natural essential oils (all described in Chen et al. (2014) Asian J. Pharm. Sc. 9, 51-64); citric acid esters such as triethyl citrate, hydrophobin polypeptides; alpha bisabolol; dimethyl isosorbide (Arlasolve® DMI); ethoxydiglycol. Propane-1,2-diol is preferred.

Typical examples for preservatives suitable for topical application are e.g. benzyl benzoates, benzoic acid, benzyl alcohol, benzalkonium chloride, tetradecyltrimethylamino bromine (cetrimide, Merck), chlorhexidine, tert-butyl chloride, chlorocresol, imidurea, parabens such as methylparaben, ethylparaben, propylparaben, butylparaben, methylparaben sodium, propylparaben sodium, potassium sorbate, sodium benzoate, sodium propionate, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, sorbic acid or thiomersal (mercurothiosalic sodium ylate). Preference is given to methylparaben, propylparaben, as well as methylparaben sodium and propylparaben sodium.

The addition of antioxidants is particularly advantageous in topical galenic forms. Suitable examples for this are sodium metabisulfite, alpha-tocopherol, ascorbic acid, maleic acid, sodium ascorbate, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, fumaric acid or propyl gallate. The use of sodium metabisulfite is preferred.

Suitable pH adjusters for topical dosage forms are, for example, sodium hydroxide, hydrochloric acid, buffer substances such as sodium biphosphate or disodium hydrogen phosphate.

Cream preparations may also contain other excipients and additives, such as fatteners, solvents, viscosizers or hydrotropic agents to improve flow behavior. Singular substances may be present in the mixture as well as several from the same group of additives or excipients.

Suitable lubricants are, for example, oleic acid decyl ester, hydrated castor oil, light mineral oil, mineral oil, polyethylene glycol, sodium dodecyl sulfate.

Suitable solvents are corn oil, cottonseed oil, peanut oil, sesame oil, soybean oil, ethyl oleate, glycerin, isopropyl myristate, isopropyl palmitate, polyethylene glycol or polypropylene glycol.

Viscous agents are, for example, cetyl alcohol, cetyl ester wax, hydrated castor oil, microcrystalline waxes, non-ionic emulsifying waxes, beeswax, paraffin or stearyl alcohol. Suitable hydrotopes are alcohols such as ethanol, isopropyl alcohol or polyols such as glycerin.

According to the invention, all of the above-mentioned excipients and classes of excipients can be used without limitation alone or in any conceivable combination thereof, provided that the inventive use of a solubilisate is not counteracted, toxic effects may occur or are infringed. the respective national legislations.

Therefore, the present application also relates to a pharmaceutical composition according to the invention for use in medicine.

The present application also relates to a pharmaceutical composition according to the invention for oral, parenteral or topical administration.

Conditions with an exaggerated immune reaction are, for example, but not limited to, rejection reactions after transplantation, active autoimmune diseases or diseases with an autoimmune component, in particular rheumatoid arthritis, relapsing-remitting multiple sclerosis, autoimmune hepatitis, polyarteritis nodosa , Crohn's disease, ulcerative colitis, dermatomyositis, Behget's syndrome, uveitis due to Behget's syndrome, immunological thrombocytopenic purpura, myasthenia gravis, Lambert-Eaton syndrome, polymyositis, psoriasis, psoriatic arthritis, ankylosing spondylitis, paroxysmal nocturnal hemoglobinuria, diseases of the autoimmune thyroid such as Hashimoto's thyroiditis, Ord's thyroiditis or Graves-Basedow disease, systemic lupus erythematosus, vitiligo, autoimmune encephalomyelitis, idiopathic optic neuritis, sympathetic ophthalmia, anterior uveitis, macular degeneration, peripheral ulcerative keratitis, bullous pemphigoid, chronic urticaria, dermatitis herpetiformis, epidermolysis bullosa acquisita, alopecia areata, autoimmune enteropathy, autoimmune polyendocrine diseases such as APECED (Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy), Schmidt syndrome, IPEX syndrome (immunodysregulation syndrome - polyendocrinopathy - X-linked enteropathy), chronic gastritis, dermatomyositis , type 1 diabetes mellitus, type 2 diabetes mellitus, Graves' ophthalmopathy, glomerulonephritis, Goodpasture syndrome, granulomatosis with polyangiitis, Guillain-Barré syndrome, lichen sclerosus, lichen planus, linear IgA dermatosis, leukocytoclastic vasculitis, myalgic encephalomyelitis, narcolepsy, PANS (pediatric acute onset neuropsychiatric syndrome) such as PANDAS (pediatric autoimmune neuropsychiatric disorder associated with streptococcus), pemphigus foliaceus, pemphigus seborrheicus, pemphigus vulgaris, relapsing polychondritis before , polymyalgia rheumatica, rheumatic fever, sA p HO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis), sarcoidosis, Sjogren's syndrome, systemic sclerosis, stiff person syndrome, Henoch-Schonlein purpura, celiac disease, acute disseminated encephalomyelitis, antiphospholipid syndrome, autoimmune cardiomyopathy, autoimmune hemolytic anemia, autoimmune internal α-dose disease, autoimmune lymphoproliferative syndrome, autoimmune pancreatitis, autoimmune polyendocrine syndrome, autoimmune progesterone dermatitis, Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic multifocal recurrent osteomyelitis, COPD (lung disease chronic obstructive), Churg-Strauss syndrome, cold agglutinin syndrome, painful adiposis, endometriosis, eosinophilic fasciitis, Hashimoto encephalopathy, acne inversa, interstitial cystitis, Kawasaki syndrome, mixed connective tissue disease, neuromyotonia, opsoclonus-myoclonus syndrome , primary biliary cirrhosis, Raynaud's disease, restless legs syndrome, transverse myelitis and vasculitis, aplastic anemia, pemphigus, pemphigoid, endogenous uveitis, nephrotic syndrome and atopic dermatitis, as well as septic conditions, e.g. caused by infections with bacteria gram-negative or gram-positive bacteria, e.g. MRSA (methicillin-resistant Staphylococcus aureus), or fungal pathogens, and systemic inflammatory response syndrome (SIRS) caused by other factors (e.g. immunological or chemical).

Conditions with an immunodeficient background include, but are not limited to, frequent influenza infections, recurrent respiratory tract infections, recurrent excretory urinary tract infections, fatigue, frailty, concentration disorders of unknown origin, convalescence, chronic viral infections, particularly influenza viruses. human immunodeficiency (e.g. HIV-1, HIV-2), hepatitis B, hepatitis C, encephalitis, herpes zoster, herpes simplex, internal α-dose infections, chickenpox, measles, cytomegaly, Epstein-Barr, adenovirus, papillomavirus human and parvovirus, such as amdovirus, bocavirus, dependovirus, erythrovirus and parvovirus spec; different oncological diseases, particularly tricholeukemia, myeloid leukemia, multiple myeloma, follicular lymphomas, Kaposi sarcoma, cutaneous T cell lymphoma, cavum carcinoma, carcinoid, renal carcinoma, bladder cancer, basaliomas, metastatic carcinomas and malignant melanoma; septic granulomatous, neutropenia; genital warts; keratosis; autoimmune diseases; particularly inactive phases, such as relapsing-remitting multiple sclerosis between exacerbations; radiogenic colitis, diverticular disease; allergies, particularly hay fever, polymorphous light dermatitis, eczema, neurodermatitis; enteritis; colitis; as well as before, during and after chemo- and radiotherapy.

In summary, a 5-amino-2,3-dihydrophthalazine-1,4-dione solubilized produced by the method of the invention is particularly suitable for the treatment of all inflammatory diseases that are characterized by a substantial increase in pro-cytokines. inflammatory, particularly IL-6 and TNF-alpha. Apart from the examples mentioned above, this is also the case in the context of wound healing, for example after surgery, trauma or burns, in immunological processes such as keratoconjunctivitis sicca or in acute or chronic inflammations of unknown origin, such as such as tendovaginitis or osteoarthritis.

A 5-amino-2,3-dihydrophthalazine-1,4-dione solubilisate produced by the method of the invention may also be administered in combination with at least one other known pharmaceutically active agent and/or standard therapy.

Therefore, the present application also relates to a combination of a solubilisate according to the invention and at least one pharmaceutically active agent.

The present application also relates to a combination of a solubilisate according to the invention and at least one pharmaceutically active agent for use in the prophylaxis and/or treatment of conditions with an excessive immune reaction or conditions with an immunodeficient background.

The pharmaceutically active agents suitable for such a combination can be selected from the group comprising steroidal and non-steroidal anti-inflammatory active ingredients, immunomodulators, immunostimulants, immunosuppressants, anti-infective active ingredients, antibiotics, antiviral agents, antifungal agents, antiprotozoal agents, anthelmintics, analgesics. , local anesthetics, anticoagulants, antiplatelet agents, muscle relaxants, tonics and anabolic agents. Such a combination of active ingredients can be used for prophylactic and/or therapeutic purposes in a person who needs it.

Suitable examples of steroidal anti-inflammatory active ingredients include corticosteroids, glucocorticoids, cortisone, cortisone acetate, hydrocortisone, hydrocortisone acetate, dexamethasone, betamethasone, prednisone, prednisolone, methylprednisolone, deltasone, triamcinolone, tixocortol pivalate, mometasone, amcinonide, budesonide, desonide, fluociconide. , fluocinolone, halciconide, fluocortolone, hydrocortisone 17-valerate, halometasone, alclomethasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone 18-butyrate, clobetasol 17-propionate, fluocortolone caproate, fluocortolone pivalate, fluprednidene acetate, hydrocortisone 17-butyrate, hydrocortisone 17-aceponate, hydrocortisone 17-buteprate, ciclesonide, flunisolide, fluticasone furoate, fluticasone propionate, triamcinolone acetonide, beclomethasone dipropionate.

Appropriate examples of non-steroidal anti-inflammatory drugs (NSAIDs) include acetylsalicylic acid, salicylic acid and salicylates, paracetamol (acetaminophen), salsalato, diflunisal, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, piroxicam, meloxi cam, tenoxicam, droxicam, lornoxicam, isoxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, firocoxib, nimesulide, clonixine, licofelone, H-harpagide, flunixin, tiaprofenic acid .

Suitable examples for immunomodulators (IMIDs) include thalidomide, lenalidomide, pomalidomide and apemilast.

Suitable examples for immunostimulant active ingredients include interferons (interferon alpha, beta, gamma, tau), interleukins, G-CSF, FCDP, EGF, IGF, THF, levamisole, dimepranol, inosine.

Suitable examples for immunosuppressive active ingredients include the group of glucocorticoids as described above; cytostatics such as alkylating agents (such as cyclophosphamide), antimetabolites such as methotrexate, azathioprine, mercaptopurine, fluorouracil, leflunomide, protein synthesis inhibitors and certain antibiotics such as dactinomycin, anthracyclines, mitomycin C, bleomycin and mithramycin, intercalating agents such as mitoxantrone ; antibodies such as muromonab-CD3, rituximab, ustekinumab, alemtuzumab, natalizumab, basiliximab and daclizumab; agents that act on immunophilins such as cyclosporine, tacrolimus and sirolimus; and unclassified immunosuppressive agents such as interferon beta, interferon-gamma, opioids, TNF binding proteins such as infliximab, etanercept, adalimumab; or curcumin, catechins, mycophenolic acid, fingolimod, myriocin and dimethyl fumarate.

Anti-infective agents is a generic term for compounds that can be used in the treatment of bacterial, viral, fungal, protozoal and worm infections, and includes antibiotics, antiviral agents, antifungals, antiprotozoal agents, anthelmintics and other antiparasitic drugs.

Suitable examples of antibiotics include imipenem, meropenem, ertapenem, cephalosporins, aztreonam, penicillins such as penicillin G and penicillin V, piperacillin, mezlocillin, ampicillin, amoxicillin, flucloxacillin, methicillin, oxacillin, clavulanic acid, sulbactam, tazobactam, sultamicillin, fosfomycin, teicoplanin, vancomycin, bacitracin, colistin, gramicidin, polymyxin B, tyrothricin, teixobactin, fosmidomycin, amikacin, gentamicin, kanamycin, neomycin, netilmycin, streptomycin, tobramycin, chloramphenicol, fusidic acid, cethromycin, narbomycin, telithromycin, clindamycin, lincomycin, daptomycin, dalfopri stin, quinupristin, azithromycin, clarithromycin, erythromycin, roxithromycin, linezolid, doxycycline, minocycline, tetracycline, oxytetracycline, tigecycline, norfloxacin, enoxacin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, metronidazole, tinidazole, aminocoumarin, sulfadiazine, sulfadoxine, sulfameto xazole, sulfasalazine, pyrimethamine, trimethoprim and rifampin.

Suitable examples of antiviral agents include ancriviroc, aplaviroc, cenicriviroc, enfuvirtide, maraviroc, vicrivirov, amantadine, rimantadine, pleconaril, idoxuridine, acyclovir, brivudine, famciclovir, penciclovir, sorivudin, valacyclovir, cidofovir, ganciclovir, valganciclovir, sofosbusvir, foscarnet, ribavirin, taribavirin, filibuvir, nesbuvir, tegobuvir, fosdevirine, faviparavir, merimepodib, asunaprevir, balapiravir, boceprevir, ciluprevir, danoprevir, daclatasvir, narlaprevir, telaprevir, simeprevir, vaniprevir, rupintrivir, fomivirsen, amenamevir, alisporivir, bevirimate, letermovir, laninamivir, oseltamivir, peramivir, zanamivir.

Suitable examples of antifungal agents include abafungin, amphotericin B, candicidin, filipin, hachymycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole. , albaconazole, efinaconazole, epoxiconazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, voriconazole, amorolfine, butenafine, nafitifine, terbinafine, anidulafungin, caspofungin, micafungin, benzoic acid, cyclopirox, flucytosine, griseofulvin, haloprogin, tolnaftate, undecylenic acid, crystal violet, balsam of Peru.

Suitable examples for antiprotozoal agents include metronidazole, tinidazole, ornidazole, atovaquone, clioquinol, chlorquinaldol, emetine, pentamidine isethionate, eflornithine, nitrofural, halofuginone, miltefosine, chloroquine, hydroxychloroquine, mepacrine, primaquine, amodiaquine, pamaquine, piperaquine, proguanil, cyclohunayl embonate, quinine, mefloquine, pyrimethamine, artemether, artemisinin, artesunate, dihydroartemisinin, halofantrine, lumefantrine, sulfadoxine.

Suitable examples of anthelmintics include mebendazole, praziquantel, albendazole, diethylcarbamazine, flubendazole, ivermectin, levamisole, metrifonate, niclosamide, oxyclozanide, oxamniquin, oxantel, piperazine, pyrantel, pyrantel pamoate, monopantel, derquantel, Pelletier quinine sulfate, pyrvinium, thiabendazole. , fenbendazole, triclabendazole, abamectin, suramin, emodepside, pyrvinium embonate, aminoacetonitril.

Suitable examples of other antiparasitic drugs include meglumine antimoniate, benznidazole, sodium stibogluconate, fumariline, halofantrine, melarsoprol, nifurtimox, nitazoxanide, permethrin, lindane, malathion, carbaryl, pyrethrum, phenothrin, bio-alletrin, imidacloprid, moxidectin, nitenpyram, fipronil. , pyriprole, selamectin, dimpilate, spinosad, indoxacarb, methoprene, pyriproxyfen, lufenuron, neem oil, citronella oil, clove oil, peppermint oil, eucalyptus oil.

Suitable examples of analgesics include the NSAIDs listed above; opioid pain relievers such as morphine, fentanyl, methadone, oxycodone, carfentanil, dihydroetorphine, ohmefentanil, etorphine, sufentanil, remifentanil, alfentanil, buprenorphine, hydromorphone, levomethadone, hydrocodone, piritramide, nalbuphine, tapentadol, pentazocine, dihydrocodeine, codeine, pethidine, tramadol, tilidine , meptazinol, naloxone, naltrexone, diprenorphine, loperamide, apomorphine; epibatidine; scopolamine; ziconotide; cannabinoids such as tetrahydrocannabinol, cannabidiol, marinel; flupirtine; ketamine and the local anesthetics listed above.

Suitable examples for local anesthetics include lidocaine, lignocaine, menthol, articaine, bupivacaine, ropivacaine, benzocaine, chloroprocaine, cocaine, cyclomethaine, dimethocaine, larocaine, piperocaine, propoxycaine, procaine, novocaine, proparacaine, tetracaine, amethocaine, cinchocaine, dibucaine, etidocaine, levobupivacaine, meplavacaine, prilocaine, trimecaine, saxitoxin, neosaxitoxin, tetrodotoxin, eugenol.

Suitable examples for anticoagulants include heparins, coumarins such as phenprocoumon (Marcumar) and warfarin, apixaban, rivaroxaban, edoxaban, dabigatran, ximelagatran, hirudin, lepirudin, bivalirudin, citrate, EDTA, fondaparinux, argatroban, otamixaban.

Suitable examples for antiplatelet agents include abciximab, acetylsalicylic acid, dipyridamole, clopidogrel, epftifibatide, ilomedin, prostacyclin, prasugrel, ticagrelor, ticlopidine, tirafiban.

Suitable examples for muscle relaxants include tercuronium, 1-ethylcarbamoyl-3-(3-trifluoromethylphenyl)pyrrolidone, metaxalone, methocarbamol, meprobamate, baclofen, carisoprodol, chloroxanzone, cyclobenzaprine, dantrolene, diazepam, orphenadrine, quinine, rocuronium, sucinylcholine, decamethonium, pancuronium. , veruronium, rapacuronium, dacuronium, duador, malouetin, dipyrandium, pipercuronium, candocuronium, HS-342, atracurium, mivacurium, doxacurium, d-tubocurarine, dimethyltubocurarine, galamine, alcuronium, anatruxonium, diadonium, fazadinium, tropeinium, cisatruxonium.

Tonics is a general term for active ingredients that strengthen the body, increase its tone or restore its physiological functions. They can be of plant or animal origin.

Anabolic agents can promote anabolic metabolism and a strengthening of the collagen cellular scaffold. However, widespread abuse of these substances as doping agents in sports and bodybuilding is known. Therefore, the combination with the crystalline form of luminol produced by the disclosed procedure is recommended only to the extent this is covered by the respective national laws.

One skilled in the art will readily identify standard therapies for the above-mentioned pharmaceutically active agents from the prior art. It is preferable that the modes of administration and the respective doses of the mentioned combinations of the pharmaceutically active agents are oriented to the standard therapies already established for the combined active agent.

Examples

In the following examples, the relative amounts of the solubilizing agents can be varied within the ranges indicated for each component in the method according to the invention. The addition of glyceryl oleate and/or antioxidant is optional.

It is possible to increase or decrease the indicated quantities according to the desired absolute quantity of the agent to be solubilized in the solubilisate. The solubilisate can be divided into portions according to the desired final amount of the agent to be administered to a patient in need.

In general, the solubilisates produced according to the method of the invention had a specific density of 0.92 -0.94 kN/m3.

In each example, the production of a dosage form for the solubilisates according to the invention is described for illustrative purposes. It is understood that the solubilisates according to the invention may also be used in any corresponding dosage form known in the art, e.g. as set forth in Remington: The Science and Practice of Pharmacy, 22nd edition, Pharmaceutical Press, 2013, which is will be incorporated as a reference.

Standard chemicals were purchased from Sigma-Aldrich, Darmstadt, Germany.

Example 1: Solubilization of 5-amino-2,3-dihydrophthalazine-1,4-dione - embodiment 1

The following indications refer to the percentage by weight of the mixture. A solubilized of ca. 100 ml. 5-amino-2,3-dihydrophthalazine-1,4-dione is provided, and then the solubilizing agents are mixed one by one under stirring for 5 minutes at room temperature (20 ± 5 °C) and atmospheric pressure.

5-amino-2,3-dihydrophthalazine-1,4-dione 2.0%

PC of non-hydrogenated soybean 46.0%

MCT oil 45.6%

mixture of 1-lysophosphatidylcholine and 2-lysophosphatidylcholine (1:1) 2.2%

ethanol 1.9%

oleic acid 0.8%

glyceryl stearate 1.2%

glyceryl oleate 0.2%

alpha-tocopherol 0.1%

The composition is then heated cautiously under continuous stirring, with a temperature increase of approximately 1 °C/min. After ca. 20 min (ca. 40 °C) the composition begins to become a clear solution. This solubilization process lasts approx. 16 more minutes. In this way, a solubilized according to the invention is obtained after approx. 36 min to ca. 56°C. Heating and stirring are then stopped and the resulting solubilized is allowed to cool to room temperature. The solubilisate remains clear and stable over an observation period of a minimum of 6 months.

Example 2: Solubilization of 5-amino-2,3-dihydrophthalazine-1,4-dione - embodiment 2

The following indications refer to the percentage by weight of the mixture. A solubilized of ca. 100 ml. 5-Amino-2,3-dihydrophthalazine-1,4-dione is provided, and then the solubilizing agents are mixed one by one under stirring for 5 minutes at room temperature (20 ± 5°C) and atmospheric pressure.

5-amino-2,3-dihydrophthalazine-1,4-dione 0.15%

1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) 60%

MCT oil 32.45%

1-lysophosphatidylcholine 2.6%

ethanol 2.2%

oleic acid 1.1%

glyceryl stearate 1.2%

glyceryl oleate 0.2%

beta-tocopherol 0.1%

The composition is then cautiously heated under continuous stirring, with an approximate temperature increase of 1.5 °C/min. After ca. 23 min (ca. 55 °C) the composition begins to become a clear solution. This solubilization process lasts approx. 10 more minutes. In this way, a solubilized according to the invention is obtained after approx. 33 min to ca. 70°C. Heating and stirring are then stopped and the resulting solubilized is allowed to cool to room temperature. The solubilisate remains clear and stable over an observation period of a minimum of 6 months.

Example 3: Solubilization of 5-amino-2.3-dihydrophthalazine-1.4-dione sodium salt

The following indications refer to the percentage by weight of the mixture. A solubilized of ca. 100 ml. 5-Amino-2,3-dihydrophthalazine-1,4-dione sodium salt (in the form of the Form I polymorph as described in WO 2011/107295 A1) is provided, and then the solubilizing agents are mixed one by one under stirring. for 5 minutes at room temperature (20 ± 5 °C) and atmospheric pressure.

5-amino-2,3-dihydrophthalazine-1,4-dione sodium salt 1.0%

CP of non-hydrogenated soybean 70.0%

MCT oil 21.6%

2-lysophosphatidylcholine 2.6%

ethanol 2.2%

oleic acid 1.1%

glyceryl stearate 1.2%

glyceryl oleate 0.2%

delta-tocopherol 0.1%

The composition is then heated cautiously under continuous stirring, with a temperature increase of approximately 1 °C/min. After ca. 32 min (ca. 52 °C) the composition begins to become a clear solution. This solubilization process lasts approx. 8 more minutes. In this way, a solubilized according to the invention is obtained after approx. 40 min to ca. 60°C. Heating and stirring are then stopped and the resulting solubilized is allowed to cool to room temperature. The solubilisate remains clear and stable over an observation period of a minimum of 2 months.

Example 4: Preparation of a liquid dosage form for oral application

In 45 ml of a liquid vehicle having the following composition (in % by weight)

water for injection 99.3% citrate buffer 0.5%

methylparaben propylparaben (5:1 ratio) 0.1%

sodium metabisulfite 0.1%

5 ml of the solubilized of Example 1 are resolved. This solution (50 ml) can be filled into an appropriate dropper bottle known in the art.

This formulation does not need an additional emulsifier such as a polysorbate.

Example 5: Preparation of a liquid dosage form for parenteral application

In 245 ml of a liquid vehicle having the following composition (in % by weight)

water for injection 98.9% sodium chloride 0.9%

methylparaben propylparaben (10:1 ratio) 0.1%

sodium metabisulfite 0.1%

5 ml of the solubilized of Example 1 are resolved. This parenteral solution (250 ml) can be filled into an appropriate infusion bag known in the art.

This formulation does not need an additional emulsifier such as a polysorbate.

Example 6: Preparation of a solid dosage form such as soft gelatin capsules

Composition of soft gelatin capsule shell (in % by weight):

gelatin 66.3% glycerin 33.0% methylparaben propylparaben (ratio 4:1) 0.1% carmoisine 0.1% titanium dioxide 0.5% aqua dest. 1.3 x gelatin A soft gelatin capsule containing a solubilized 5-amino-2,3-dihydrophthalazine-1,4-dione salt is produced according to standard methods, as set out in: Mahato and Narang, Pharmaceutical Dosage Forms and Drug Delivery, 2nd ed,, chap. 18.3.5. Here 1.25 ml of the solubilisate of Example 1 is injected into the mold cavity of the provided soft gelatin capsule which is then sealed.

Example 7: Preparation of a solid dosage form such as hard gelatin capsules

Composition of hard gelatin capsule shell (in % by weight):

gelatin 85.0%

water 14.3%

methylparaben propylparaben (ratio 4:1) 0.1%

twilight yellow 0.1%

titanium dioxide 0.5%

Hard gelatin capsules (size "000", having a volume of 1.4 ml) are produced by a standard method known in the art. 1.25 ml of the solubilized as produced in Example 1 are filled into a capsule, respectively. The two pieces of hard gelatin capsules are then assembled.

Example 8: Preparation of a topical dosage form such as a cream

The following ingredients are used (in % by weight):

5-amino-2,3-dihydrophthalazine-1,4-dione solubilized, such as in Example 1 3.00% cetearyl alcohol (Lanette D®) 6.60% glyceryl stearate (Cutina MD®) 4.15% ceteareth 20 (Eumulgin B2®) 0.40%

ceteareth 12 (Eumulgin B1®) 1.25 % decyl oleate (Cetiol V®) 2.50% allantoin 0.15% sodium cetearyl sulfate (Lanette E®) 0.65% glycerin 20.70% phenoxyethanol, dehydroacetic acid, acid benzoic acid (Rokonsal ND®) 1.00% water 59.60% In a first preparation, the solubilized of 5-amino-2,3-dihydrophthalazine-1,4-dione, cetearyl alcohol, glyceryl stearate, ceteareth 20, ceteareth 12, decyl oleate and sodium cetearyl sulfate are mixed and heated to 70 °C. In a second allantαn preparation, glycerin and water are mixed and heated to 70°C. Then, the first preparation and the second preparation are slowly mixed and homogenized with a disperser (Ultra-Turrax T-18®) for 2 -3 min. When it cools to 35 °C, a third preparation consisting of Rokonsal ND® is added and stirred homogeneously. The mixture is homogenized again at ca. 45 °C for 1 min. Then the resulting mixture is allowed to cool to room temperature under stirring, avoiding the inclusion of air. If necessary, the pH can be adjusted with NaOH or citric acid.

The pH of the cream is 5.40. The stability of the skin cream was minimum 6 months at 40 °C. At this temperature no phase separation occurred.

50 ml of the resulting cream are packaged in a suitable collapsible aluminum tube known in the art.

Example 9: Preparation of a topical dosage form as a hydrogel

A hydrogel is generated by slight modifications of the method disclosed in US 2010/0129448 A1.

A 3% CMC (carboxymethyl cellulose) solution is prepared by mixing 5 ml of the solubilized of Example 1 with API (water for injection) followed by autoclaving to completely dissolve the CMC in solution, resulting in the formation of a CMC hydrogel. A suspension is prepared by adding said solubilized solution in ApI to the CMC hydrogel. Stabilizers (TEA, citric acid) are added to the CMC hydrogel. The resulting blend is mixed under high shear conditions (paddle mixer and sonication) as described in US 2005/0175707 at elevated temperature (40 to 50°C). Glycerol and additional API are also added to the suspension. The amount of excipients added to the hydrogel is controlled to achieve a desired concentration containing 5-amino-2,3-dihydrophthalazine-1,4-dione.

The 3% CMC hydrogel suspension is further mixed for 20 minutes, resulting in the formation of a bulk hydrogel suspension. The bulk hydrogel suspension is observed under an optical microscope at 100x magnification. The primary particle size of the suspended particles is less than ca. 10 μm, thus allowing topical application of the composition to open wounds or other tissues without abrasion.

Example 10: Preparation of a solid dosage form as a suppository

Composition of the suppository base (in % by weight):

cocoa butter 97.9%

ascorbic acid 0.1%

aluminum monostearate 2.0%

1) For fusion, the base of the suppository is heated to 50 - 52 °C. The molten fat base is then slowly cooled to 36°C.

2) For each suppository to be molded, the respective amount of 0.5 ml of the solubilized of Example 3 is added to the fatty base. A soft base is formed.

3) Said soft base is filled into a suppository mold configured for the production of 3 cm long torpedo-shaped rectal suppositories having a weight of approx. 2 g.

4) The suppositories are allowed to cool to room temperature and then collected.

The use of the solubilizer according to the invention allows the production of suppositories without the use of an additional emulsifier and/or a plasticizer. Therefore, said suppository according to the invention is free of polysorbate.

Claims (16)

1. A method for solubilizing 5-amino-2,3-dihydrophthalazine-1,4-dione, comprising the following steps: a) Provide 5-amino-2,3-dihydrophthalazine-1,4-dione in the general range of 0.1% to 25% by weight at room temperature and a pressure of 0.2 bar to 1 bar; b) Add the solubilization agents in any sequence. at least one phosphatidylcholine in the total range of 20% to 80% by weight, at least one medium chain triglyceride in the total range of 10% to 70% by weight, at least one lysophosphatidylcholine in the total range of 1% to 15% by weight, at least one C ² to C ⁴ alcohol in the total range of 1% to 20% by weight, and at least one of glyceryl stearate and/or a saturated or unsaturated C ¹⁴ to C ²⁰ fatty acid in the total range of 0.5% to 10% by weight, respectively, wherein the relative weight percentages of all ingredients add up to 100% and all solubilizing agents are a food additive and/or pharmaceutically acceptable excipient; c) Carefully heat the resulting mixture by continuously increasing the temperature with a continuous increase of 0.5 °C / min to 3 °C / min over a period of 20 to 60 minutes; d) Stop the temperature increase in a temperature range of 30 °C to 125 °C as soon as a clear solution is reached; and e) Let the resulting solubilized cool to room temperature. 2. The method according to claim 1, wherein 5-amino-2,3-dihydrophthalazine-1,4-dione is provided in the form of sodium, potassium or lithium salt or a mixture thereof in the total range of 0.1% to 2% by weight at room temperature and a pressure of 0.2 bar to 1 bar. 3. The method according to claim 1 or 2, wherein said at least one saturated or unsaturated C ¹⁴ to C ²⁰ fatty acid is oleic acid. 4. The method according to any one of claims 1 to 3, wherein said at least one C ² to C ⁴ alcohol is ethanol. 5. The method according to any one of claims 1 to 4, wherein additionally in step b) at least one antioxidant is added in the total range of 0.01 to 10% by weight, wherein said at least one antioxidant It is a pharmaceutically acceptable excipient. 6. The method according to claim 5, wherein said at least one antioxidant is ascorbyl palmitate and/or at least one tocopherol. 7. A solubilized of 5-amino-2,3-dihydrophthalazine-1,4-dione, comprising 5-amino-2,3-dihydrophthalazine-1,4-dione provided in the general range of 0.1% to 25% by weight at room temperature and a pressure of 0.2 bar to 1 bar; at least one phosphatidylcholine in the total range of 20% to 80% by weight, at least one medium chain triglyceride in the total range of 10% to 70% by weight, at least one lysophosphatidylcholine in the total range of 1% to 15% by weight, at least one C ² to C ⁴ alcohol in the total range of 1% to 20% by weight, and at least one of glyceryl stearate and/or a saturated or unsaturated C ¹⁴ to C ²⁰ fatty acid in the total range of 0.5% to 10% by weight, respectively, wherein the relative weight percentages of all ingredients add up to 100% and all solubilizing agents are a food additive and/or pharmaceutically acceptable excipient and the solubilisate is free of polysorbate. 8. The solubilizer according to claim 7, wherein 5-amino-2,3-dihydrophthalazine-1,4-dione is provided in the form of a sodium, potassium or lithium salt or a mixture thereof in the total range of 0.1% to 2% by weight at room temperature and a pressure of 0.2 bar to 1 bar. 9. The solubilized according to claim 7 or 8 for prophylactic or therapeutic use in medicine. 10. The solubilisate as defined in one of claims 7 to 9 for use as an immunomodulator to treat conditions with an excessive immune reaction or conditions with an immunodeficient background. 11. The solubilized as defined in one of claims 9 to 10 for prophylactic or therapeutic use to improve the absorption and/or bioavailability of 5-amino-2,3-dihydrophthalazine-1,4-dione. 12. A pharmaceutical composition containing 5-amino-2,3-dihydrophthalazine-1,4-dione formulated in a solubilized as defined in claim 7 or 8 and at least one pharmaceutically acceptable excipient. 13. A pharmaceutical composition according to claim 12, wherein said pharmaceutical composition is suitable for oral, parenteral or topical administration. 14. The combination of a solubilized as defined in claim 7 or 8 and at least one pharmaceutically active agent selected from a group comprising steroidal and non-steroidal anti-inflammatory active ingredients, immunomodulators, immunostimulants, immunosuppressants, antibiotics, anti-inflammatory active ingredients. infectives, antiviral agents, antifungal agents, antiprotozoal agents, anthelmintics, analgesics, local anesthetics, anticoagulants, antiplatelet agents, muscle relaxants, tonics and anabolic agents for use in the prophylaxis and/or treatment of conditions with an excessive immune reaction or conditions with an immunocompromised background. 15. A pharmaceutical composition according to claim 12, wherein said at least one pharmaceutically acceptable excipient is selected from a group comprising vehicles, binders, lubricants, glidants, disintegrants, colorants, buffers, preservatives, emulsifiers, permeation enhancers, antioxidants , diluents, pH adjusters, greasers, solvents, viscosizers, hydrotropic agents, sweeteners, acidulants, thickeners, non-stick agents, fillers, flavorings, sweeteners, opacifiers, flavorings and aromatic substances. 16. A pharmaceutical composition according to claim 12 or 15 for use in medicine.